Rosmarinic acid protects against MPTP-induced toxicity and inhibits iron-induced α-synuclein aggregation

Abstract

&NA; Rosmarinic acid (RA) is a naturally occurring polyphenolic compound. In this study, we demonstrated that RA could protect against the degeneration of the nigrostriatal dopaminergic system in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced mouse model of Parkinson s disease (PD). In addition, RA could inhibit MPTP‐induced decrease of superoxide dismutase (SOD) and tyrosine hydroxylase (TH) and increase in nigral iron content. Further studies elucidated the effects of RA on iron‐induced neurotoxicity and the possible underlying mechanisms in the SK‐N‐SH cells. Results showed that iron could induce a decrease in the mitochondrial transmembrane potential and result in &agr;‐synuclein aggregation in the SK‐N‐SH cells, which could be restored by RA pretreatment. Further results showed RA pretreatment could inhibit iron‐induced &agr;‐synuclein aggregation by up‐regulating hemeoxygenase‐1 (HO‐1). In addition, iron could increase the mRNA levels of &agr;‐synuclein via iron responsive element/iron regulatory protein (IRE/IRP) system. RA pretreatment could decrease the mRNA levels of &agr;‐synuclein by decreasing the protein levels of IRP1. These results indicated that RA protected against iron‐induced &agr;‐synuclein aggregation by up‐regulating HO‐1 and inhibiting &agr;‐synuclein expression. HIGHLIGHTSRA protected DA neurons against MPTP by decreasing iron levels and enhancing SOD expression.RA pretreatment could restore iron‐induced reduction of &Dgr;Ψm and &agr;‐synuclein aggregation.RA pretreatment could inhibit iron induced &agr;‐synuclein aggregation by up‐regulating HO‐1.RA protected against iron‐induced &agr;‐synuclein expression by IRE/IRP system.